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CN1330653A - 4,5-pyrazinoxindoles as protein kinase inhibitors - Google Patents

4,5-pyrazinoxindoles as protein kinase inhibitors Download PDF

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CN1330653A
CN1330653A CN99814597A CN99814597A CN1330653A CN 1330653 A CN1330653 A CN 1330653A CN 99814597 A CN99814597 A CN 99814597A CN 99814597 A CN99814597 A CN 99814597A CN 1330653 A CN1330653 A CN 1330653A
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heteroaryl
lower alkyl
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CN1158283C (en
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陆建春
克里斯托夫·米舒
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F Hoffmann La Roche AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

4,5-pyrazinoxindoles having formula (I), inhibit or modulate protein kinases, in particular JNK protein kinases and are useful as anti-inflammatory agents, particularly in the treatment of rheumatoid arthritis.

Description

4-and 5-pyrazinyl oxindole as kinases inhibitor
Protein kinase is the protein that a class is regulated the various kinds of cell function.This phosphorylated by specific amino acids on protein substrate realizes, causes the configuration of substrate protein to change.Configuration changes the interaction ability regulated the active of substrate or itself and other binding partner.The enzymic activity of protein kinase is meant that kinases is added to speed on the substrate with phosphate.It can, for example, measure as the amount of substrate that is converted into product of the function of time by measuring.The phosphorylated of substrate takes place at the avtive spot of protein kinase.
JNK (Jun N-holds kinases) protein kinase (being also referred to as " stress-activated protein kinase " or " SAPK ") is the short kinase whose member of former activated protein (MAP) that separates.Referring to, for example, S.Gupta etc., EMBO J., 15 volumes, No.11, (1996) 2760-2770 page or leaf; With yang etc., nature, 289 volume (1997, October 23) 865-870 pages or leaves.Have at least ten kinds of JNK isotypes be current oneself know.Above-mentioned document referring to Gupta.Shown in its title, one of substrate of JNK is c-Jun.JNK makes NH2-end region of activation phosphorylated on Ser63 and Ser73 of c-Jun, and the c-Jun transcriptional activity is increased.Above-mentioned document referring to Gupta.In addition, c-Jun is the AP-1 transcription factor that the mediation immediate early gene is expressed.Referring to, for example, A.Minden etc., Biochimica et Biophysica Acta1333 (1997) F85-F104; With A.Karin etc., Biochimica et Biophysica Acta, 1072 volume (1991) 129-157 pages or leaves.
The JNK protein kinase is obviously being activated when handling cellular response with pro-inflammatory cytokine or being in environmental stress.Therefore, the extracellular stimulus effect of JNK mediation on c-Jun.Above-mentioned document referring to Gupta.Therefore, JNK is the physiological regulation agent of AP-1 transcriptional activity.The active inhibition of JNK will suppress and proliferative disorders, and for example the dependence AP-1's of relevant inflammation of inflammation and neurodegeneration (neuro-degenerative) disease, particularly rheumatic arthritis and amboceptor,immune transcribes.Referring to, Swantek etc. for example, molecular cytobiology, 17 volumes (1997), 6274-6282 page or leaf; Maroney etc., J.Neuroscience, 18 volumes (1998, January 1), 104-111 page or leaf; With the above-mentioned document of Minden, F92.
The rat homologue of JNK is also referred to as SAPK (stress activated protein kinase).(＞90%) sequence identity [comparing Kyriakis etc., nature, 369 volumes (1994, May 12), the above-mentioned document of 156-160 page or leaf and Gupta] that the SAPK isotype is total important with corresponding JNK isotype.JNK and SAPK can both make c-Jun substrate phosphorylated, thereby have closely similar enzymic activity.JNK and SAPK are by the part of various extracellular stimulus activated protein kinase cascade.Above-mentioned document referring to for example Minden; With Kyriakis etc., BioEssays 18 volumes (1996), 567-577 page or leaf.JNK and SAPK separately can be by by dual specific map kinase kinases such as MKK4, SEK-1, or MKK7 phosphorylated and activating on specific Threonine and tyrosine residues.Above-mentioned document referring to Kyriakis etc.; With Tournier etc., Proceedings of the National Academy of ScienceUSA94 rolls up (in July, 1997), the 7337-7342 page or leaf.Dual specific map kinase kinases can be by phosphorylated on Serine and/or threonine residues activates by map kinase kinases such as MEKK-1.Therefore, the measurement of JNK or SAPK enzymic activity can be by being strengthened by the upstream or the kinase whose activation that ranks forefront.And it is closely related that measurement that SAPK suppresses and JNK suppress.
The inhibitor of protein kinase catalytic activity is known in the art.Referring to WO98/24432 (dihydroindole compounds that suppresses the FLK protein kinase); WO97/45409 (the tetralyl methylene radical-oxindole homologue that suppresses the replacement of Tyrosylprotein kinase).Particularly, micromolecular inhibitor is typically blocked combining of substrate by interacting securely with protein kinase A TP binding site (or " activation site ").Referring to WO98/24432.Need identification to synthesize easily, and effectively arrestin kinases, the especially micromolecular compound of the catalytic activity of JNK protein kinase.
Be proved can be used for through Tyrosylprotein kinase suppress and the dihydroindolone (being also referred to as oxindole) of dysregulation hyperplasia at for example WO96/40116, WO98/07695, WO95/01349, WO96/32380, WO96/22976 WO96/16964 and WO98/50356 (as the 2-indolinone derivative of protein kinase activity conditioning agent); Mohammadi etc., science, 276 volumes, on May 9th, 1997, open in the 955-960 page or leaf.Oxindole derivatives has also been described various other therepic use: 5206261 (improving brain function); WO92/07830 (peptide antagonists); EP580502A1 (antioxidant).
Need to synthesize easily always, can effectively suppress the JNK protein kinase and can be used for treatment or the micromolecular compound of control pathology proliferative disease (for example inflammation and neurodegenerative disease, especially rheumatic arthritis).An object of the present invention is to provide this compounds and the composition that contains this compounds.
The present invention relates to suppress the 4-and the 5-pyrazinyl oxindole of one or more JNK protein kinase activities.These compounds are used for the treatment of inflammation and neurodegenerative disease.Particularly, compound of the present invention is used in particular for treatment or control rheumatic arthritis.
Compound of the present invention is the 4-and the 5-pyrazinyl oxindole of following formula: And the acceptable salt of medicine, wherein
R 1And R 2The separate group group that is selected from down:
Hydrogen,
-OR 4，
-COR 4，
-COOR 4，
-CONR 5R 6，
-NR 5R 6，
Low alkyl group, it can be consisted of OR 4,-NR 5R 6, halogen ,-COR 4,-COOR 4,-OCOR 4,-CONR 5R 6,-CN ,-SO 2R 4,-SO 2NR 5R 6Group (a) in a group replace; Perhaps replaced by cycloalkyl, heterocycle, aryl and heteroaryl, wherein cycloalkyl and heterocycle can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace,
Cycloalkyl, a group in the group (a) that it can be defined as above replaces; Perhaps replaced by low alkyl group, heterocycle, aryl and heteroaryl, wherein low alkyl group and heterocycle can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace,
Heterocycle, a group in the group (a) that it can be defined as above replaces; Perhaps replaced by low alkyl group, cycloalkyl, aryl and heteroaryl, wherein low alkyl group and cycloalkyl can be respectively by radicals R 11Replace, aryl and heteroaryl can be chosen wantonly by radicals R respectively 12Replace,
Aryl, it can be consisted of OR 4,-NR 5R 6, halogen ,-NO 2, perfluoroalkyl ,-COR 4,-COOR 4,-OCOR 4,-CONR 5R 6,-CN ,-SO 2R 4,-SO 2NR 5R 6Group (b) in a group replace; Perhaps replaced by low alkyl group, cycloalkyl, heterocycle, aryl and heteroaryl, wherein low alkyl group, cycloalkyl and heterocycle can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace,
Heteroaryl, a group in the group (b) that it can be defined as above replaces; Perhaps replaced by low alkyl group, cycloalkyl, heterocycle, aryl and heteroaryl, wherein low alkyl group, cycloalkyl and heterocycle can be chosen wantonly by radicals R respectively 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace, perhaps
R 1And R 2Can form the ring with 5 to 7 atoms, described ring is optional to comprise one or more heteroatomss, and is optionally replaced by a group in the group down :-OR 8,-COR 7,-COOR 7,-OCOR 4,-CONR 7R 9,-NR 8R 9Or low alkyl group (it can be by radicals R 11Replace);
R 3Be hydrogen ,-OR 4,-COR 4,-COOR 4,-OCOR 4,-CONR 5R 6, halogen ,-CN, perfluoroalkyl ,-NR 5R 6, or low alkyl group (it can be by-OR 4,-OCOR 4Or-NR 5R 6Replace);
R 4Be hydrogen,
Low alkyl group, it can be consisted of OR 8,-COOR 7,-COR 7,-CONR 5R 6,-NR 5R 6,-SO 2R 7,-SO 2NR 5R 6Group (c) in a group replace; Perhaps replaced by cycloalkyl, heterocycle, aryl and heteroaryl, wherein cycloalkyl and heterocycle can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace,
Cycloalkyl, a group in the group (c) that it can be defined as above replaces; Perhaps replaced by low alkyl group, heterocycle, aryl and heteroaryl, wherein low alkyl group and heterocycle can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace,
Heterocycle, a group in the group (c) that it can be defined as above replaces; Perhaps replaced by cycloalkyl, low alkyl group, aryl and heteroaryl, wherein cycloalkyl and low alkyl group can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace,
Aryl, it can be consisted of OR 8,-COOR 7,-COR 7,-CONR 5R 6,-NR 5R 6,-NO 2, halogen, perfluoroalkyl ,-SO 2R 7,-SO 2NR 5R 6Group (d) in a group replace; Perhaps replaced by low alkyl group, cycloalkyl, heterocycle, aryl and heteroaryl, wherein low alkyl group, cycloalkyl and heterocycle can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace and
Heteroaryl, a group in the group (d) that it can be defined as above replaces; Perhaps replaced by cycloalkyl, low alkyl group, heterocycle, aryl and heteroaryl, wherein low alkyl group, cycloalkyl and heterocycle can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace,
R 5And R 6Independently be respectively:
Hydrogen,
-COR 7，
-COOR 7，
-CONR 7R 9，
Low alkyl group, it can be consisted of OR 8,-COOR 7,-COR 7,-CONR 7R 8,-NR 7R 8,-SO 2R 7,-SO 2NR 7R 8Group (e) in a group replace; Perhaps replaced by cycloalkyl, heterocycle, aryl and heteroaryl, wherein cycloalkyl and heterocycle can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace,
Cycloalkyl, a group in the group (e) that it can be defined as above replaces; Perhaps replaced by low alkyl group, heterocycle, aryl and heteroaryl, wherein low alkyl group and heterocycle can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace,
Heterocycle, a group in the group (e) that it can be defined as above replaces; Perhaps replaced by cycloalkyl, low alkyl group, aryl and heteroaryl, wherein cycloalkyl and low alkyl group can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace,
Aryl, it can be consisted of OR 8,-COOR 7,-COR 7,-CONR 7R 8,-NR 7R 8,-NO 2, halogen, perfluoroalkyl ,-SO 2R 7,-SO 2NR 7R 8Group (f) in a group replace; Perhaps replaced by low alkyl group, cycloalkyl, heterocycle, aryl and heteroaryl, wherein low alkyl group, cycloalkyl and heterocycle can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace, and
Heteroaryl, a group in the group (f) that it can be defined as above replaces; Perhaps replaced by cycloalkyl, low alkyl group, heterocycle, aryl and heteroaryl, wherein low alkyl group, cycloalkyl and heterocycle can be respectively by radicals R 11Replace, aryl and heteroaryl can be respectively by radicals R 12Replace, perhaps
-NR 5R 6Can form the ring with 3 to 7 atoms, described ring is optional to comprise one or more other heteroatomss, and optional by low alkyl group ,-OR 8,-COR 7,-COOR 7,-CONR 7R 9, or-NR 8R 9Replace;
R 7Be hydrogen or low alkyl group, its can by under organize one of group and replace: cycloalkyl, heterocycle, aryl, heteroaryl ,-OR 9Or-NR 8R 9
R 8Be hydrogen ,-COR 9,-CONR 10R 9, or can be by R 11Replace low alkyl group;
R 9And R 10Be hydrogen or low alkyl group independently of one another;
R 11Be-OR 9,-COR 9,-COOR 9,-OCOR 9,-CONR 9R 10,-NR 9R 10,-N (COR 9) R 10,-SO 2R 9, or-SO 2NR 9R 10
R 12Be-OR 9,-COR 9,-COOR 9,-OCOR 9,-CONR 9R 10,-NR 9R 10,-N (COR 9) R 10,-SO 2R 9,-SO 2NR 9R 10, halogen ,-CN ,-NO 2Or perfluoroalkyl; With
X is N or CH.
The invention still further relates to any or multiple above-claimed cpd that comprises pharmacy effective dose and the pharmaceutical composition of medicine acceptable carrier or vehicle.
The invention still further relates to the new intermediate that is used for synthetic above-claimed cpd.
The invention still further relates to formula I compound and/or its salt, prodrug or pharmaceutical activity metabolite is used for the treatment of and/or controls inflammation and neurodegenerative disease (particularly rheumatic arthritis) or be used for the treatment of application in the medicine of solid tumour (particularly mammary gland or colon tumor) in preparation.
Term used herein has as giving a definition.
" aryl " refers to have 5 to 10 atoms and encircles the aromatic base of forming by 1 or 2.The example of aryl comprises phenyl and 1-or 2-naphthyl.
" cycloalkyl " refers to contain the non-fragrance of 3 to 8 atoms, partially or completely saturated cyclic aliphatic hydrocarbon.The example of cycloalkyl comprises cyclopropyl, cyclopentyl and cyclohexyl.
" significant quantity " refers to the amount of at least a formula I compound or the acceptable salt of its medicine, prodrug or metabolite, can suppress the development or the hyperplasia of (1) inflammatory disease or reaction and/or (2) neurodegenerative disease or reaction (for example being not limited to rheumatic arthritis).
" halogen " refers to fluorine, chlorine, bromine or iodine.
" heteroaryl " is to have 5 to 10 atoms, 1 or 2 ring and contain one or more heteroatomic aromatic bases.The example of heteroaryl has 2-, 3-or 4-pyridyl, tetrazyl ， oxadiazole base, pyrazinyl, quinolyl, pyrryl and imidazolyl.
" heteroatoms " refers to be selected from N, the atom of O and S.
" heterocycle " refers to the non-fragrance of 3-to 10-unit, contains one or two ring and at least one heteroatomic partially or completely saturated alkyl, and as tetrahydric quinoline group, it contains one or two ring, at least one heteroatoms.
" IC 50" referring to suppress 50% the needed concrete 4-of cJun phosphorylated and the concentration of 5-pyrazinyl oxindole, it is the active criterion that suppresses of SAPK.IC 50Especially can adopt this paper embodiment 7 described detections to measure.
" low alkyl group " refers to have 1 to 6, the straight or branched aliphatic saturated hydrocarbon of preferred 1 to 4 carbon atom.Typical low alkyl group comprises methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 2-butyl, amyl group, hexyl etc.
" the acceptable salt of medicine " has referred to keep the biopotency and the character of formula I or II compound, and the conventional acid additive salt or the base addition salt that are formed by suitable non-toxic organic or mineral acid or organic or inorganic alkali.The example of acid salt comprises from mineral acid example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, dithiocarbamic acid, phosphoric acid and nitric acid deutero-salt with from deutero-salt such as organic acid such as tosic acid, Whitfield's ointment, methylsulfonic acid, oxalic acid, succsinic acid, citric acid, oxysuccinic acid, lactic acid, fumaric acid.The example of base addition salt comprises from the oxyhydroxide of ammonium, potassium, sodium and quaternary ammonium, for example tetramethyl ammonium hydroxide deutero-salt.
" pharmaceutically acceptable " as pharmaceutically acceptable carrier, vehicle, prodrug etc., refers to that pharmacology is acceptable and to the essentially no toxicity of the patient of administration particular compound.
" pharmaceutical active metabolite " refers to the meta-bolites of pharmaceutically acceptable and effective formula I compound.
" prodrug " refers under physiological condition or can be converted into any formula I compound or be converted into the compound of the acceptable salt of medicine of formula I compound by solvolysis.When to patient's administration, prodrug can be a non-activity, but it is converted into the active compound of formula I in vivo.
" replacement " alkyl as replacing unless otherwise indicated, refers to that substituting group can exist in one or more positions, and substituting group is independently selected from concrete option.
According to the present invention, preferred perfluoroalkyl comprises-CF 3
In the preferred embodiment of formula I compound, R 1And R 2Independently be
Hydrogen,
-NR 5R 6，
Low alkyl group, it can be by R 11, cycloalkyl, heterocycle, aryl and heteroaryl replace, wherein cycloalkyl and heterocycle can be by R 11Replace, aryl and heteroaryl can be by R 12Replace;
Cycloalkyl, it can be by R 11, low alkyl group, heterocycle, aryl and heteroaryl replace, wherein low alkyl group and heterocycle can be by R 11Replace, aryl and heteroaryl can be by R 12Replace;
Heterocycle, it can be by R 11, low alkyl group, cycloalkyl, aryl and heteroaryl replace, wherein low alkyl group and cycloalkyl can be by R 11Replace, aryl and heteroaryl can be by R 12Replace;
Aryl, it can be by R 12, low alkyl group, cycloalkyl, heterocycle, aryl and heteroaryl replace, wherein low alkyl group, cycloalkyl and heterocycle can be by R 11Replace, aryl and heteroaryl can be by R 12Replace;
Heteroaryl, it can be by R 12, low alkyl group, cycloalkyl, heterocycle, aryl and heteroaryl replace, wherein low alkyl group, cycloalkyl and heterocycle can be by R 11Replace, aryl and heteroaryl can be by R 12Replace; Perhaps R 1And R 2Can form the ring with 5 to 7 atoms, described ring is optional to be replaced by group in the following group :-OR 8,-COR 7,-COOR 7,-CONR 7R 9,-NR 8R 9With can be by R 11The low alkyl group that replaces.
More specifically, R 1And R 2Independent is low alkyl group, and aryl is phenyl particularly, or heterocycle furyl particularly, or R 1And R 2Form ring, particularly cyclohexane ring together with 5-7 atom.
In another preferred embodiment of formula I compound, R 3Be hydrogen ,-OR 4, NR 5R 6, or can be by group-OR 4With-NR 5R 6The low alkyl group that replaces.
In another preferred embodiment of formula I compound, R 3Be hydrogen ,-OR 9, or can be by group-OR 9With-NR 9R 10The low alkyl group that replaces.R 3Lower alkoxy more preferably.
Classify the example of formula I preferred compound down as:
(Z)-7,9-dihydro-2,3-dimethyl-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone (A),
(Z)-3-butyl-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-2-methyl-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone and (Z)-2-butyl-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-3-methyl-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone (B)
(Z)-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-2-methyl-3-phenyl-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone and (Z)-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-3-methyl-2-phenyl-8H-pyrrolo--[3,2-f] quinoxaline-8-ketone (C)
(Z)-7,9-dihydro-2,3-two-(2-furyl)-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone (D),
(Z)-1,3,5,6,7, methylene radical 8-six hydrogen-3-[(3-methoxyl group-1H-pyrroles-2-yl)]-2H-pyrrolo-[3,2-a] azophenlyene-2-ketone (E).
Disclosed herein and can be had tautomerism or Structural Isomerism by the compound that following formula covers.The present invention includes any tautomerism or the Structural Isomerism form of these compounds, or the mixture of this class form, applied any tautomerism or Structural Isomerism form in the formula scope that is not limited to provide in the above.
Formula I compound can prepare by methods known in the art.The suitable method that is used for synthetic these compounds embodiment below provides.In general, these compounds can be according to following route of synthesis preparation.Steps A
Figure A9981459700151
Step B
Figure A9981459700152
Figure A9981459700153
Figure A9981459700154
Step e
Figure A9981459700161
In another optional scheme, the present invention relates to comprise the pharmaceutical composition of the prodrug of the drug acceptable salt of at least a formula I compound or its prodrug or formula I compound or this compounds.
These pharmaceutical compositions can be taken orally, for example with tablet, and coated tablet, sugar-pill, hard or soft capsule, solution, emulsion or form of suspension administration.They also can rectal administration, and for example with the suppository form administration, perhaps administered parenterally is for example with the injection solution form administration.
Comprising the prodrug of formula I compound, this compounds or the pharmaceutical composition of the present invention of its salt can for example mix by conventional with this professional known method production, the glue capsule, and dissolving is granulated, and emulsification captures, sugaring ball, or lyophilization preparation.These pharmaceutical preparations can the inorganic or organic carrier preparation with the treatment inert.Lactose, W-Gum or derivatives thereof, talcum, stearic acid or its salt can be used as tablet, coated tablet, the carrier of sugar-pill and hard capsule.The suitable carrier of soft capsule has vegetables oil, wax, fat, semisolid or liquid poll.According to the character of active substance, under the situation of soft capsule generally without carrier.Producing solution or the used carrier of syrup is water, how pure, sucrose, Nulomoline and glucose.The suitable carrier of injection liquid is a water, and how pure alcohol is, glycerine, vegetables oil, phosphatide and tensio-active agent.The suitable carrier of suppository be natural or hardened oily, wax, fat and semisolid is how pure.
Pharmaceutical preparation also can contain sanitas, solubilizing agent, stablizer, wetting agent, emulsifying agent, sweeting agent, tinting material, seasonings, salt, buffer reagent, Drug coating or the antioxidant of change osmotic pressure.They also can contain the material that other has therapeutic value, comprise other activeconstituents outside the formula I compound.
As mentioned above, formula I or II compound, its prodrug, its salt and contain these compound compositions can be used for the treatment or control inflammation and neurodegenerative disease, especially the treatment or control rheumatic arthritis.
The treatment significant quantity of The compounds of this invention refers to can effectively prevent, slow down or improve the amount of being treated the patient disease symptom.The treatment significant quantity fixes in this professional ken really.
The treatment significant quantity of formula I compound or dosage can change in very wide restriction, and can regulate according to individual need under various particular cases.In general, under the situation to the one-tenth human oral of the about 70kg of body weight or administered parenterally, the about 10mg of per daily dose is to about 10000mg, and preferably about 200mg extremely about 1000mg will be suitable, and when indicating, the upper limit can be exceeded.Per daily dose can divide single dose or multiple dose administration, perhaps for administered parenterally, and can continous pouring.
The compounds of this invention can synthesize as the general way that provides above according to known technology.The following example illustrates the preferred method that is used for synthetic The compounds of this invention and preparation.Below, r.t. is a room temperature, and EtOH is an ethanol, and MeOH is a methyl alcohol, and THF is a tetrahydrofuran (THF).Embodiment 1: general synthesis method and starting raw material general method A:(Z)-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-preparation of 8H-pyrrolo-[3,2-f] quinoxaline-8-ketone
(60mg 0.22mmo1) in EtOH (3mL) suspension of (starting raw material 5), adds 10 normal diketone, and after the heating, suspension is converted into heavier organic solid to initial diamino derivative.Cooling mixture at room temperature, suction filtration collecting precipitation, dried overnight in vacuum drying oven.Asymmetric diketone obtains the mixture of regional isomer (regioisomer).Starting raw material 1:1,3-dihydro-4-fluoro-2H-indol-2-one
Figure A9981459700172
With 6-fluoro-2-nitrobenzyl prussiate (23.10g, 0.12mole) (according to A.Kalir etc., synthetic, 1987,514-515) be dissolved in 10: 1 MeOH/H 2Among the O (250mL), this solution of cooling in ice-water bath.In the refrigerative mixture, fed HBr75 minute.Solution is warming up to room temperature, under reduced pressure is concentrated into half of its volume then.At room temperature add THF (100mL), water (100mL) and concentrated hydrochloric acid (6mL) continuously, keep and stirred 75 minutes.Mixture is poured in the water, used ethyl acetate extraction.Merge organic phase, water, saturated NaHCO 3The aqueous solution and salt water washing then by dried over sodium sulfate, under reduced pressure concentrate.This material (20.9g) is dissolved in the acetate (200mL) hydrogenation 2 hours in the presence of 50Psi, the 10%Pd/C (4.33g) in the Parr device.This reaction mixture is filtered by Celite  filter cake (Fisher Scientific), filter cake is washed with acetate.Solution is under reduced pressure concentrated, be dissolved among the MeOH (300mL) that contains 1N NaOH (15mL).Pour mixture into 2: 1 saturated MeOH/H 2In O (600mL) aqueous solution, use ethyl acetate extraction.Merge organic phase, use the salt water washing, dried over sodium sulfate also concentrates.The crude product residue is ground with ether, obtain 5.8g (first) pure 1,3-dihydro-4-fluoro-2H-draws diindyl-2-ketone.Mother liquor is crossed silica gel chromatography (the 230-400 order is with 40% ethyl acetate/hexane wash-out), obtains the other product of 1.6g (prussiate overall yield: 41%).Starting raw material 2:1,3-dihydro-4-fluoro-5-nitro-2H-draws diindyl-2-ketone
Figure A9981459700181
With 1,3-dihydro-4-fluoro-2H-draws diindyl-2-ketone, and (6.29g, 41.6mmol) (above-mentioned starting raw material 1) under agitation is dissolved in dense H 2SO 4In.Cooling mixture is to-20 ℃ in dry ice-propanone is bathed, in 30 minutes to wherein slowly adding 2.6mL (41.6mmol) HNO 310mL HSO 4In the solution.Afterwards in 45 minutes (the TLC:50% ethyl acetate/hexane shows complete reaction after 30 minutes) of-20 ℃ of following stirred reaction mixtures, pour into then in the 1L frozen water, with 2 * 200mL ethyl acetate extraction, the washing of 2 * 200mL saturated nacl aqueous solution, dried over sodium sulfate, under 45 ℃, high vacuum, concentrate, obtain brown solid (7.87g).With this material recrystallization in ethyl acetate, obtain 3.94g (only first) pure products.Mother liquor is crossed silica gel chromatography (the 230-400 order is with 50% ethyl acetate/hexane wash-out), obtains the other product of 1.91g (overall yield: 5.85g, 71.7%).Starting raw material 3:(Z)-1, methylene radical 3-dihydro-4-fluoro-3-[(3-methoxyl group-1H-pyrroles-2-yl)]-5-nitro-2H-indol-2-one
With 1, (5.25g, 26.8mmol) (starting raw material 2) is suspended in 2-propyl alcohol (Fisher) solution of 110mL 1.35% piperidines (Aldrich) 3-dihydro-4-fluoro-5-nitro-2H-indol-2-one.Add 3-methoxyl group-2-pyrroles's carboxylic aldehyde (carboxaldehyde) (3.68g, 29.4mmol, 1.1 equivalents) (according to F.Bellamy etc., J.Chem.Research (S) 1979,18-19; J.Chem.Research (M), 1979, the 0101-0116 preparation), this mixture is heated 3.5 hours (TLC:50% ethyl acetate/hexane) down at 60 ℃.Reaction mixture is poured in the 1L mixture of ice and water, filtered solid precipitation, wash with water, drying obtains orange-brown solid product (productive rate 6.6g, 81%) under 50C, the high vacuum.Starting raw material 4:(Z)-and 4-azido--1,3-dihydro-3-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-2H-draws diindyl-2-ketone
Figure A9981459700192
At room temperature with (Z)-1,3-dihydro-4-fluoro-3-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-(6.60g, 21.8mmol) (above-mentioned starting raw material 3) is suspended in 330mLTHF and the 165mL ethanol 5-nitro-2H-indol-2-one.Add diisopropylethylamine (56.9ml, 326mmol) (Aldrich) and trimethyl silane trinitride (28.6mL, 218mmol) (Aldrich) to mixture.With reaction mixture heated overnight under refluxing, pour into then in the mixture of 2L ice and 1N HCl solution.Filter solid precipitation, wash with water, drying obtains garnet solid (Z)-4-azido--1,3-dihydro-3-[(3-methoxyl group-1H-pyrroles-2-yl under 50 ℃, high vacuum) methylene radical]-2H-indol-2-one (productive rate 6.44g, 90%).Starting raw material 5:(Z)-4,5-diaminostilbene, 3-dihydro-3-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-the 2H-indol-2-one
Figure A9981459700201
At room temperature with (Z)-4-azido--1,3-dihydro-3-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-(2.08g, 6.37mmol) (above-mentioned starting raw material 4) is dissolved among the THF (160mL) the 2H-indol-2-one.Add ammonium hydroxide (2mL), add the toxicity platinum on carbon (5%Pt/C1/2S, 300mg) (the Engelhard Ind.) of catalytic amount then.With the hydrogenation 12 hours under 50psi hydrogen in the Parr high-pressure cylinder of this mixture.By Celite  cake filtration, with filter cake THF washed twice, filtrate under reduced pressure concentrates with this mixture.Crude product flash chromatography on silica gel (flash chromatography) purifying (230-400 order, with 75% ethyl acetate/hexane wash-out), obtain (Z)-4, the 5-diaminostilbene, 3-dihydro-3-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-2H-draws diindyl-2-ketone (productive rate 1.44g, 84%).Embodiment 2:(Z)-7,9-dihydro-2,3-dimethyl-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone (A)
Figure A9981459700202
Use aforesaid method A, under refluxing with (Z)-4,5-diaminostilbene, 3-dihydro-3-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-the 2H-indol-2-one (60mg, 0.22mmol) (starting raw material 5) with in ethanol (3mL) 2,3-dimethyl diketone (135 μ L) (Aldrich) concentrates, obtain (Z)-7,9-dihydro-2,3-dimethyl-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone, productive rate 100%.Embodiment 3:(Z)-3-butyl-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-2-methyl-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone and (Z)-2-butyl-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-mixture (B) of 3-methyl-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone
Use aforesaid method A, under refluxing with (Z)-4, the 5-diaminostilbene, 3-dihydro-3-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-2H-indol-2-one (60mg, 0.22mmol) (starting raw material 5) with in ethanol (3mL) 2,3-heptadione (282 μ L) (Lancaster) concentrates, obtain (Z)-3-butyl-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-2-methyl-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone and (Z)-2-butyl-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-mixture of 3-methyl-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone, productive rate 88%.Embodiment 4:(Z)-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-2-methyl-3-phenyl-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone and (Z)-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-mixture (C) of 3-methyl-2-phenyl-8H-pyrrolo--[3,2-f] quinoxaline-8-ketone
Figure A9981459700212
Use aforesaid method A, under refluxing with (Z)-4, the 5-diaminostilbene, 3-dihydro-3-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-2H-indol-2-one (60mg, 0.22mmol) (starting raw material 5) and the 1-phenyl-1 in ethanol (3mL), 2-propanedione (326 μ L) (Aldrich) concentrates, obtain (Z)-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-2-methyl-3-phenyl-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone and (Z)-7,9-dihydro-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-mixture of 3-methyl-2-phenyl-8H-pyrrolo--[3,2-f] quinoxaline-8-ketone, productive rate 46%.Embodiment 5:(Z)-7,9-dihydro-2,3-two-(2-furyl)-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone (D)
Figure A9981459700221
Use aforesaid method A, under refluxing with (Z)-4, the 5-diaminostilbene, 3-dihydro-3-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-the 2H-indol-2-one (60mg, 0.22mmol) (starting raw material 5) is (Aldrich) concentrated with the Kang Ouxian (200mg) in ethanol (3mL), obtains (Z)-7,9-dihydro-2,3-two-(2-furyl)-9-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-8H-pyrrolo-[3,2-f] quinoxaline-8-ketone, productive rate 86%.Embodiment 6:(Z)-1,3,5,6,7, methylene radical 8-six hydrogen-3-[(3-methoxyl group-1H-pyrroles-2-yl)]-2H-pyrrolo-[3,2-a] azophenlyene-2-ketone (E)
Figure A9981459700222
Use aforesaid method A, under refluxing with (Z)-4, the 5-diaminostilbene, 3-dihydro-3-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-the 2H-indol-2-one (60mg, 0.22mmol) (starting raw material 5) with in ethanol (3mL) 1,2-cyclohexanedione (248mg) (Aldrich) concentrates, obtain (Z)-1,3,5,6,7,8-six hydrogen-3-[(3-methoxyl group-1H-pyrroles-2-yl) methylene radical]-2H-pyrrolo-[3,2-a] azophenlyene-2-ketone, productive rate 18%.It is active that embodiment 7:SAPK suppresses
The SAPK of The compounds of this invention suppresses active following proof.These effects show that The compounds of this invention can be used for treating inflammation, for example rheumatic arthritis.
The test of SAPK Flash board
People's JNK and the SAPK of rat height homology.For the inhibition activity of experiment with measuring compound, compound in analyzing, is tested rat SAPK.In order to measure the active inhibition of SAPK, the GST-c-Jun (chimeric protein that contains cJun, the natural substrate of JNK) that purifying is crossed be coated on the 96 hole Flash boards (New England Nuclear, Boston, MA).The rat SAPK that purifying is crossed (isotype β, the aforementioned documents of Kyriakis etc.) is containing 25mMHEPES, pH7.5,150mM NaCl, 20mM MgCl with the preparation that contains MEKK-1 and MKK4 2, 2mM DTT, 0.001%Tween20, initiate 1 μ M ATP the test damping fluid in 37 ℃ of preincubation 30 minutes.In the preincubation step, the MEKK-1 phosphorylated also activates MKK-4, turn back phosphorylated and activate SAPK of the latter.Activatory SAPK with 33P-ATP and compound are added into the Flash board that was coated with cJun then.37 ℃ of incubations 30 minutes, (Packard Instrument Co., DowneersGrove IL) went up counting then with PBS, 0.01%Tween 20 washings, and at the Topcount scintillometer with this plate.The diluent of test compound is repeated test in various tests.The cJun phosphorylated suppresses percentage ratio (the active criterion that suppresses of SAPK) and measures according to following formula:
100 * 1-[(test compound-non-specific number)/(sum-non-specific number)] wherein " test compound " finger to finger test repeats the average counter of per minute, " non-specific number " refers to the per minute average counter when not adding SAPK, and " sum " average counter of per minute when referring to not add compound.
The result of various test compound SAPK tests provides in Table I.The PC01221 Table I
Compound ????SAPK
% suppresses Concentration (μ M)
????A ????≥50％ ????<0．1
????B ????≥50％ ????0.5
????C ????≥50％ ????0.5
????D ????≥50％ ????0.5
????E ????≥50％ ????<0.1
Embodiment 8: tablet formulation
Project Composition The mg/ sheet
????1 Compound 1 * ????5 ????25 ????100 ????250 ????500 ????750
????2 Lactose hydrous 103 ?83 ?35 ?19 ?38 ?57
????3 Croscarmellose sodium 6 ?6 ?8 ?16 ?32 ?48
????4 ?Povidone?K30 ????5 ????5 ????6 ????12 ????24 ????36
????5 Magnesium Stearate ????l ????1 ????1 ????3 ????6 ????9
Gross weight 120 ?120 ?150 ?300 ?600 ?900
* compound 1 is represented The compounds of this invention.Production technique: 1. project 1,2 and 3 was mixed 15 minutes in suitable mixing tank.2. the powdered mixture of step 1 is granulated with 20%Povidone K30 solution (project 4).3. at the particle of 50 ℃ of drying step 2.4. the particle with step 3 installs by suitable grinding (milling).5. project 5 is added in the particle of the step 4 after grinding, and mixed 3 minutes.6. with particle compressing tablet on suitable tabletting machine of step 5.
Embodiment 9: capsule formula PC01221
Project Composition The mg/ capsule
????1 Compound 1 * ????5 ????25 ????100 ????250 ????500
????2 Lactose hydrous ????159 ????123 ????148 ????-- ????--
????3 W-Gum ????25 ????35 ????40 ????35 ????70
????4 Talcum ????10 ????15 ????10 ????12 ????24
????5 Magnesium Stearate ????1 ????2 ????2 ????3 ????6
Gross weight ????200 ????200 ????300 ????300 ????600
* compound 1 is represented The compounds of this invention.Production technique: 1. project 1,2 and 3 was mixed 15 minutes in suitable mixing tank.2. adding project 4 and 5 and mixed 3 minutes.3. be filled in the capsule.Embodiment 10: injection liquid/emulsion
Project Composition ????mg/ml
????1 Compound 1 * ????1mg
????2 ????PEG?400 ????10-50mg
????3 Phosphatide ????20-50mg
????4 Soya-bean oil ????1-5mg
????5 Glycerine ????8-12mg
????6 Water adds to ????1ml
* compound 1 is represented The compounds of this invention.Production technique: 1. project 1 is dissolved in the project 2.2. with project 3,4 and 5 adding projects 6 and be mixed to dispersion, homogenizing then.3. the solution with step 1 adds in the mixture of step 2, and homogenizing is transparent to dispersion liquid.4. aseptic filtration 0.2 μ m filter paper also is filled in the bottle.Embodiment 11: injection liquid/emulsion
Project Composition ???mg/ml
????1 Compound 1 * ????1mg
????2 ????Glycofurol ??10-50mg
????3 Phosphatide ??20-50mg
????4 Soya-bean oil ???1-5mg
????5 Glycerine ???8-12mg
????6 Water Add to 1ml
* compound 1 is represented The compounds of this invention.Production technique: 1. project 1 is dissolved in the project 2.2. with project 3,4 and 5 adding projects 6 and be mixed to dispersion, homogenizing then.3. the solution with step 1 adds in the mixture of step 2, and homogenizing is transparent to dispersion liquid.4. aseptic filtration 0.2 μ m filter paper also is filled in the bottle.

Claims (15)

1.下式化合物 1. Compounds of the following formula 其中，R1和R2相互独立选自下组基团：Wherein, R 1 and R 2 are independently selected from the following groups: 氢，hydrogen, -OR4，-OR 4 , -COR4，-COR 4 , -COOR4，-COOR 4 , -CONR5R6，-CONR 5 R 6 , -NR5R6，-NR 5 R 6 , 低级烷基，其可以被组成为OR4、-NR5R6、卤素、-COR4、-COOR4、-OCOR4、-CONR5R6、-CN、-SO2R4、-SO2NR5R6的组(a)中的一个基团所取代；或者被环烷基、杂环、芳基和杂芳基取代，其中环烷基和杂环可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代；Lower alkyl, which can be formed as OR 4 , -NR 5 R 6 , halogen, -COR 4 , -COOR 4 , -OCOR 4 , -CONR 5 R 6 , -CN, -SO 2 R 4 , -SO 2 NR 5 R 6 is substituted by a group in group (a); or substituted by cycloalkyl, heterocycle, aryl and heteroaryl, wherein cycloalkyl and heterocycle may be substituted by group R 11 , respectively, Aryl and heteroaryl may be substituted by group R 12 respectively; 环烷基，其可以被如上限定的组(a)中的一个基团所取代；或者被低级烷基、杂环、芳基和杂芳基取代，其中低级烷基和杂环可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代；Cycloalkyl, which may be substituted by a group in group (a) as defined above; or substituted by lower alkyl, heterocyclic, aryl and heteroaryl, wherein lower alkyl and heterocyclic may be respectively replaced by Group R 11 is substituted, aryl and heteroaryl may be substituted by group R 12 respectively; 杂环，其可以被如上限定的组(a)中的一个基团所取代；或者被低级烷基、环烷基、芳基和杂芳基取代，其中低级烷基和环烷基可以分别被基团R11取代，芳基和杂芳基可以分别任选被基团R12取代；Heterocycle, which may be substituted by a group in group (a) as defined above; or substituted by lower alkyl, cycloalkyl, aryl and heteroaryl, wherein lower alkyl and cycloalkyl may be respectively The group R 11 is substituted, and the aryl and heteroaryl groups can each be optionally substituted by a group R 12 ; 芳基，其可以被组成为OR4、-NR5R6、卤素、-NO2、全氟烷基、-COR4、-COOR4、-OCOR4、-CONR5R6、-CN、-SO2R4、-SO2NR5R6的组(b)中的一个基团所取代；或者被低级烷基、环烷基、杂环、芳基和杂芳基取代，其中低级烷基、环烷基和杂环可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代，Aryl, which can be composed of OR 4 , -NR 5 R 6 , halogen, -NO 2 , perfluoroalkyl, -COR 4 , -COOR 4 , -OCOR 4 , -CONR 5 R 6 , -CN, - Substituted by a group in group (b) of SO 2 R 4 , -SO 2 NR 5 R 6 ; or substituted by lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein lower alkyl , cycloalkyl and heterocycle may be substituted by group R 11 respectively, aryl and heteroaryl may be substituted by group R 12 respectively, 杂芳基，其可以被如上限定的组(b)中的一个基团所取代；或者被低级烷基、环烷基、杂环、芳基和杂芳基取代，其中低级烷基、环烷基和杂环可以分别任选被基团R11取代，芳基和杂芳基可以分别被基团R12取代，或者Heteroaryl, which may be substituted by a group in group (b) as defined above; or by lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein lower alkyl, cycloalkane The radical and the heterocycle may each be optionally substituted by a group R , and the aryl and heteroaryl may each be substituted by a group R , or 可选择地，R1和R2可以形成具有5至7个原子的环，所述环任选包括一个或多个杂原子，并且任选被下组中的一个基团所取代：-OR8、-COR7、-COOR7、-OCOR4、-CONR7R9、-NR8R9或可以被基团R11取代的低级烷基；Alternatively, R 1 and R 2 may form a ring having 5 to 7 atoms, which ring optionally includes one or more heteroatoms, and is optionally substituted with one of the following groups: -OR 8 , -COR 7 , -COOR 7 , -OCOR 4 , -CONR 7 R 9 , -NR 8 R 9 or lower alkyl which may be substituted by the group R 11 ; R3是氢，-OR4，-COR4，-COOR4，-OCOR4，-CONR5R6，卤素，-CN，全氟烷基，-NR5R6，或可以被-OR4、-OCOR4或-NR5R6取代的低级烷基；R 3 is hydrogen, -OR 4 , -COR 4 , -COOR 4 , -OCOR 4 , -CONR 5 R 6 , halogen, -CN, perfluoroalkyl, -NR 5 R 6 , or can be replaced by -OR 4 , -OCOR 4 or -NR 5 R 6 substituted lower alkyl; R4是氢， R4 is hydrogen, 低级烷基，其可以被组成为OR8、-COOR7、-COR7、-CONR5R6、-NR5R6、-SO2R7、-SO2NR5R6的组(c)中的一个基团所取代；或者被环烷基、杂环、芳基和杂芳基取代，其中环烷基和杂环可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代，A lower alkyl group which may be formed into the group (c) of OR 8 , -COOR 7 , -COR 7 , -CONR 5 R 6 , -NR 5 R 6 , -SO 2 R 7 , -SO 2 NR 5 R 6 or substituted by cycloalkyl, heterocycle, aryl and heteroaryl, wherein cycloalkyl and heterocycle can be substituted by group R 11 respectively, and aryl and heteroaryl can be respectively replaced by Group R 12 is substituted, 环烷基，其可以被组(c)中的一个基团所取代；或者被低级烷基、杂环、芳基和杂芳基取代，其中低级烷基和杂环可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代，Cycloalkyl, which may be substituted by a group in group (c); or substituted by lower alkyl, heterocyclic, aryl and heteroaryl, wherein lower alkyl and heterocyclic may be respectively substituted by the group R 11 Substituted, aryl and heteroaryl groups may be substituted by groups R 12 , respectively, 杂环，其可以被组(c)中的一个基团所取代；或者被环烷基、低级烷基、芳基和杂芳基取代，其中环烷基和低级烷基可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代，Heterocycle, which may be substituted by a group in group (c); or substituted by cycloalkyl, lower alkyl, aryl and heteroaryl, wherein cycloalkyl and lower alkyl may be respectively replaced by the group R 11 Substituted, aryl and heteroaryl groups may be substituted by groups R 12 , respectively, 芳基，其可以被组成为OR8、-COOR7、-COR7、-CONR5R6、-NR5R6、-NO2、卤素、全氟烷基、-SO2R7、-SO2NR5R6的组(d)中的一个基团所取代；或者被低级烷基、环烷基、杂环、芳基和杂芳基取代，其中低级烷基、环烷基和杂环可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代，和Aryl, which can be composed of OR 8 , -COOR 7 , -COR 7 , -CONR 5 R 6 , -NR 5 R 6 , -NO 2 , halogen, perfluoroalkyl, -SO 2 R 7 , -SO 2 NR 5 R 6 is substituted by a group in group (d); or substituted by lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein lower alkyl, cycloalkyl and heterocycle may each be substituted by a group R 11 , the aryl and heteroaryl groups may each be substituted by a group R 12 , and 杂芳基，其可以被组(d)中的一个基团所取代；或者被环烷基、低级烷基、杂环、芳基和杂芳基取代，其中低级烷基、环烷基和杂环可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代，Heteroaryl, which may be substituted by a group in group (d); or by cycloalkyl, lower alkyl, heterocycle, aryl and heteroaryl, wherein lower alkyl, cycloalkyl and hetero rings may be substituted by groups R 11 , respectively, aryl and heteroaryl groups may be substituted by groups R 12 , respectively, R5和R6分别独立为：R 5 and R 6 are respectively independently: 氢，hydrogen, -COR7，-COR 7 , -COOR7，-COOR 7 , -CONR7R9，-CONR 7 R 9 , 低级烷基，其可以被组成为OR8、-COOR7、-COR7、-CONR7R8、-NR7R8、-SO2R7、-SO2NR7R8的组(e)中的一个基团所取代；或者被环烷基、杂环、芳基和杂芳基取代，其中环烷基和杂环可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代，A lower alkyl group which may be formed into the group (e) of OR 8 , -COOR 7 , -COR 7 , -CONR 7 R 8 , -NR 7 R 8 , -SO 2 R 7 , -SO 2 NR 7 R 8 or substituted by cycloalkyl, heterocycle, aryl and heteroaryl, wherein cycloalkyl and heterocycle can be substituted by group R 11 respectively, and aryl and heteroaryl can be respectively replaced by Group R 12 is substituted, 环烷基，其可以被如上限定的组(e)中的一个基团所取代；或者被低级烷基、杂环、芳基和杂芳基取代，其中低级烷基和杂环可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代，Cycloalkyl, which may be substituted by a group in group (e) as defined above; or substituted by lower alkyl, heterocycle, aryl and heteroaryl, wherein lower alkyl and heterocycle may be respectively replaced by Group R 11 is substituted, aryl and heteroaryl may be substituted by group R 12 , respectively, 杂环，其可以被如上限定的组(e)中的一个基团所取代；或者被环烷基、低级烷基、芳基和杂芳基取代，其中环烷基和低级烷基可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代，Heterocycle, which may be substituted by a group in group (e) as defined above; or substituted by cycloalkyl, lower alkyl, aryl and heteroaryl, wherein cycloalkyl and lower alkyl may be respectively The group R 11 is substituted, and the aryl and heteroaryl groups may be substituted by the group R 12 , respectively, 芳基，其可以被组成为OR8、-COOR7、-COR7、-CONR7R8、-NR7R8、-NO2、卤素、全氟烷基、-SO2R7、-SO2NR7R8的组(f)中的一个基团所取代；或者被低级烷基、环烷基、杂环、芳基和杂芳基取代，其中低级烷基、环烷基和杂环可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代，和Aryl, which can be composed of OR 8 , -COOR 7 , -COR 7 , -CONR 7 R 8 , -NR 7 R 8 , -NO 2 , halogen, perfluoroalkyl, -SO 2 R 7 , -SO 2 NR 7 R 8 is substituted by a group in group (f); or substituted by lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein lower alkyl, cycloalkyl and heterocycle may each be substituted by a group R 11 , the aryl and heteroaryl groups may each be substituted by a group R 12 , and 杂芳基，其可以被如上限定的组(f)中的一个基团所取代；或者被低级烷基、环烷基、杂环、芳基和杂芳基取代，其中低级烷基、环烷基和杂环可以分别被基团R11取代，芳基和杂芳基可以分别被基团R12取代，或者可选择地，Heteroaryl, which may be substituted by a group in group (f) as defined above; or by lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein lower alkyl, cycloalkane The radical and the heterocycle can be respectively substituted by the group R 11 , the aryl and the heteroaryl can be respectively substituted by the group R 12 , or alternatively, -NR5R6可以形成具有3至7个原子的环，所述环任选包括一个或多个其它杂原子，并且任选被低级烷基，-OR8，-COR7，-COOR7，-CONR7R9，和-NR8R9取代；-NR 5 R 6 can form a ring having 3 to 7 atoms, said ring optionally including one or more other heteroatoms, and optionally surrounded by lower alkyl, -OR 8 , -COR 7 , -COOR 7 , -CONR 7 R 9 , and -NR 8 R 9 are substituted; R7是氢或低级烷基，其中低级烷基可以被下组基团之一取代：环烷基、杂环、芳基、杂芳基、-OR9或-NR8R9；R 7 is hydrogen or lower alkyl, wherein lower alkyl can be substituted by one of the following groups: cycloalkyl, heterocycle, aryl, heteroaryl, -OR 9 or -NR 8 R 9 ; R8是氢，-COR9，-CONR10R9，或可以被R11取代低级烷基；R 8 is hydrogen, -COR 9 , -CONR 10 R 9 , or can be replaced by R 11 lower alkyl; R9和R10各自独立地是氢或低级烷基；R 9 and R 10 are each independently hydrogen or lower alkyl; R11是-OR9，-COR9，-COOR9，-OCOR9，-CONR9R10，-NR9R10，-N(COR9)R10，-SO2R9，或-SO2NR9R10；R 11 is -OR 9 , -COR 9 , -COOR 9 , -OCOR 9 , -CONR 9 R 10 , -NR 9 R 10 , -N(COR 9 )R 10 , -SO 2 R 9 , or -SO 2 NR9R10 ; R12是-OR9，-COR9，-COOR9，-OCOR9，-CONR9R10，-NR9R10，-N(COR9)R10，-SO2R9，-SO2NR9R10，卤素，-CN，-NO2或全氟烷基；和R 12 is -OR 9 , -COR 9 , -COOR 9 , -OCOR 9 , -CONR 9 R 10 , -NR 9 R 10 , -N(COR 9 )R 10 , -SO 2 R 9 , -SO 2 NR 9 R 10 , halogen, -CN, -NO 2 or perfluoroalkyl; and X是-N-或-C-，X is -N- or -C-, 以及式I化合物的前体药物和药物活性代谢物；和上述化合物的药物可接受的盐。As well as prodrugs and pharmaceutically active metabolites of compounds of formula I; and pharmaceutically acceptable salts of the above compounds. 2.权利要求1的化合物，其中2. The compound of claim 1, wherein R1和R2独立为 R1 and R2 are independently 氢，hydrogen, -NR5R6，-NR 5 R 6 , 低级烷基，其可以被R11、环烷基、杂环、芳基和杂芳基取代，其中环烷基和杂环可以被R11取代，芳基和杂芳基可以被R12取代；Lower alkyl, which may be substituted by R 11 , cycloalkyl, heterocycle, aryl and heteroaryl, wherein cycloalkyl and heterocycle may be substituted by R 11 , aryl and heteroaryl may be substituted by R 12 ; 环烷基，其可以被R11、低级烷基、杂环、芳基和杂芳基取代，其中低级烷基和杂环可以被R11取代，芳基和杂芳基可以被R12取代；Cycloalkyl, which may be substituted by R 11 , lower alkyl, heterocycle, aryl and heteroaryl, wherein lower alkyl and heterocycle may be substituted by R 11 , aryl and heteroaryl may be substituted by R 12 ; 杂环，其可以被R11、低级烷基、环烷基、芳基和杂芳基取代，其中低级烷基和环烷基可以被R11取代，芳基和杂芳基可以被R12取代；Heterocycle, which may be substituted by R 11 , lower alkyl, cycloalkyl, aryl and heteroaryl, wherein lower alkyl and cycloalkyl may be substituted by R 11 , aryl and heteroaryl may be substituted by R 12 ; 芳基，其可以被R12、低级烷基、环烷基、杂环、芳基和杂芳基取代，其中低级烷基、环烷基和杂环可以被R11取代，芳基和杂芳基可以被R12取代；Aryl, which may be substituted by R 12 , lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein lower alkyl, cycloalkyl and heterocycle may be substituted by R 11 , aryl and heteroaryl The group can be replaced by R 12 ; 杂芳基，其可以被R12、低级烷基、环烷基、杂环、芳基和杂芳基取代，其中低级烷基、环烷基和杂环可以被R11取代，芳基和杂芳基可以被R12取代；或者可选择地，R1和R2可以形成具有5至7个原子的环，所述环任选被下组中基团所取代：-OR8、-COR7、-COOR7、-CONR7R9、-NR8R9和可以被R11取代的低级烷基。Heteroaryl, which may be substituted by R 12 , lower alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, wherein lower alkyl, cycloalkyl and heterocycle may be substituted by R 11 , aryl and heterocycle The aryl group may be substituted by R 12 ; or alternatively, R 1 and R 2 may form a ring having 5 to 7 atoms, which ring is optionally substituted by groups in the group: -OR 8 , -COR 7 , -COOR 7 , -CONR 7 R 9 , -NR 8 R 9 and lower alkyl which may be substituted by R 11 . 3.权利要求2的化合物，其中R3是氢，-OR4，NR5R6，或可以被基团-OR4和-NR5R6取代的低级烷基。3. The compound of claim 2, wherein R3 is hydrogen, -OR4 , NR5R6 , or lower alkyl which may be substituted by the groups -OR4 and -NR5R6 . 4.权利要求2的化合物，其中R3是氢，-OR9，或可以被基团-OR9和-NR9R10取代的低级烷基。4. The compound of claim 2, wherein R3 is hydrogen, -OR9 , or lower alkyl which may be substituted by the groups -OR9 and -NR9R10 . 5.权利要求1的化合物，其为(Z)-7，9-二氢-2，3-二甲基-9-[(3-甲氧基-1H-吡咯-2-基)亚甲基]-8H-吡咯并[3，2-f]喹喔啉-8-酮。5. The compound of claim 1, which is (Z)-7,9-dihydro-2,3-dimethyl-9-[(3-methoxy-1H-pyrrol-2-yl)methylene ]-8H-pyrrolo[3,2-f]quinoxalin-8-one. 6.权利要求1的化合物，其为(Z)-3-丁基-7，9-二氢-9-[(3-甲氧基-1H-吡咯-2-基)亚甲基]-2-甲基-8H-吡咯并[3，2-f]喹喔啉-8-酮。6. The compound of claim 1, which is (Z)-3-butyl-7,9-dihydro-9-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2 -Methyl-8H-pyrrolo[3,2-f]quinoxalin-8-one. 7.权利要求1的化合物，其为(Z)-2-丁基-7，9-二氢-9-[(3-甲氧基-1H-吡咯-2-基)亚甲基]-3-甲基-8H-吡咯并[3，2-f]喹喔啉-8-酮。7. The compound of claim 1, which is (Z)-2-butyl-7,9-dihydro-9-[(3-methoxy-1H-pyrrol-2-yl)methylene]-3 -Methyl-8H-pyrrolo[3,2-f]quinoxalin-8-one. 8.权利要求1的化合物，其为(Z)-7，9-二氢-9-[(3-甲氧基-1H-吡咯-2-基)亚甲基]-2-甲基-3-苯基-8H-吡咯并[3，2-f]喹喔啉-8-酮。8. The compound of claim 1, which is (Z)-7,9-dihydro-9-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-methyl-3 -Phenyl-8H-pyrrolo[3,2-f]quinoxalin-8-one. 9.权利要求1的化合物，其为(Z)-7，9-二氢-9-[(3-甲氧基-1H-吡咯-2-基)亚甲基]-3-甲基-2-苯基-8H-吡咯并-[3，2-f]喹喔啉-8-酮。9. The compound of claim 1, which is (Z)-7,9-dihydro-9-[(3-methoxy-1H-pyrrol-2-yl)methylene]-3-methyl-2 -Phenyl-8H-pyrrolo-[3,2-f]quinoxalin-8-one. 10.权利要求1的化合物，其为(Z)-7，9-二氢-2，3-二-(2-呋喃基)-9-[(3-甲氧基-1H-吡咯-2-基)亚甲基]-8H-吡咯并[3，2-f]喹喔啉-8-酮。10. The compound of claim 1, which is (Z)-7,9-dihydro-2,3-bis-(2-furyl)-9-[(3-methoxyl-1H-pyrrole-2- base) methylene]-8H-pyrrolo[3,2-f]quinoxalin-8-one. 11.权利要求1的化合物，其为(Z)-1，3，5，6，7，8-六氢-3-[(3-甲氧基-1H-吡咯-2-基)亚甲基]-2H-吡咯并[3，2-a]吩嗪-2-酮。11. The compound of claim 1, which is (Z)-1,3,5,6,7,8-hexahydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene ]-2H-pyrrolo[3,2-a]phenazin-2-one. 12.含有作为活性成分的权利要求1-11中任何一个化合物和药物可接受的载体或赋形剂的药物组合物。12. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1-11 and a pharmaceutically acceptable carrier or excipient. 13.权利要求1-11中任何一个的化合物用作医药，特别是用于治疗和/或控制炎症和神经变性疾病特别是风湿性关节炎，或用于治疗实性肿瘤特别是乳腺或结肠肿瘤中的应用。13. Compounds according to any one of claims 1-11 for use as medicine, especially for the treatment and/or control of inflammatory and neurodegenerative diseases, especially rheumatoid arthritis, or for the treatment of solid tumors, especially breast or colon tumors in the application. 14.如权利要求1-11中任何一个所限定的式I化合物或其药物可接受的盐在制备含有这些化合物并且用于治疗和/或控制炎症和神经变性疾病特别是风湿性关节炎、或用于治疗实性肿瘤特别是乳腺或结肠肿瘤的医药中的应用。14. As defined in any one of claims 1-11, a compound of formula I or a pharmaceutically acceptable salt thereof is used in the preparation of these compounds and is used for the treatment and/or control of inflammation and neurodegenerative diseases, especially rheumatoid arthritis, or Use in medicine for the treatment of solid tumors, especially breast or colon tumors. 15.如上所描述的本发明。15. The invention as hereinbefore described.
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